Ornithine decarboxylase
(ODC)

ODC1
EC Number: EC 4.1.1.17

Gene: maps to 2p25 (Radford D.M. et al., 1987). It is divided into 12 exons and spans 8 kb. The first 148 bp of the 5'-flanking region contain a TATA box, cAMP-responsive element, CCAAT box, and AP-2 binding site, consistent with induction of ODC gene expression by both the cAMP and protein kinase C-mediated signaling pathways. The first intron of the human gene is 2,849 bp in length, and contains two putative Sp1 binding sites, as well as an Ap1 binding site, suggesting a role for the first intron in transcriptional regulation.
mRNA: size: ? kb.
Protein: ODC is a key enzyme in polyamines biosynthesis, catalyzing the conversion of L-ornithine into putrescine. It is found in very limited amounts in quiescent cell, although its activity rapidly and markedly increases in response to many trophic stimuli (hormones, growth factors, and tumor promoters) and during tissue regeneration (Russell D.H., 1985). Polyamines (putrescine, spermine, spermidine) are critical for cell proliferation, differentiation and transformation, and are involved in DNA, RNA, and protein synthesis, as well as in stabilizing membrane and cytoskeletal structures.
It has been postulated that the ODC gene may act as an oncogene because the overexpression of this gene is essential for cell transformation (Auvinen M. et al., 1992; Moshier J.S. et al., 1993). Overexpression of ODC by stimulating the translation of its mRNA seems to be also critical in neoplastic transformation (Shantz L.M. and Pegg A.E., 1994). Overexpression of ODC may also lead to increased tumor invasiveness and angiogenesis (Smith M.K. et al., 1997; Auvinen M., 1997).

Cell lines:
- ODC gene dosage was analyzed by Southern blot hybridization and was found to be 4- to 12-fold higher in T-47D, MDA-MB-231, and BT-20 BCC lines than in the MCF-7 BCC line. ODC mRNA level was 2- to 3-fold higher in BT-20 and MDA-MB-231 BCC lines than in the other two lines. ODC activity and polyamine concentration were also measured in these cell lines, their sensitivity to an ODC inhibitor, difluoromethylornithine (DFMO), was determined. BT-20 cells showed significantly higher ODC activity and polyamine concentrations than the other three BCC lines. BT-20 cells were resistant to the growth inhibitory effect of DFMO even at 4 mM concentration, whereas the proliferation of MCF-7, T47D, and MDA-MB-231 cells was inhibited by this drug. These results suggest that different transcriptional and post-transcriptional mechanisms control the regulation of ODC gene expression in breast cancer cell lines (Thomas T. et al., 1991).

- ODC mRNA levels was found to be higher in ER- MDA-MB-231 than in ER+ MCF-7 breast cancer cell (BCC) line. The pattern of ODC mRNA in MDA-MB-231 xenografts was polarized to the extreme periphery of the tumor, whereas the distribution of ODC mRNA was more evenly distributed in MCF-7 xenografts, suggesting that ER+ and ER- xenografts have a differential dependence on host vasculature for growth factor supply (Wright P.S. et al., 1995).

- It has been suggested that ODC expression in BCC is primarily regulated by tyrosine kinase- and protein kinase C-dependent pathways, whereas estrogens increase ODC activity through synergistic interaction with growth factors that results in a decreased rate of enzyme turnover (Huber M. and Poulin R., 1996).

- In the EGF receptor-rich MDA-MB-468 BCC, EGF was able to reduce cell growth, to induce the inhibitor of cyclin-dependent kinases, p21/CIP1/WAF1, to inhibit the peak activities of two key enzymes of polyamine biosynthesis, ODC and S-adenosylmethionine decarboxylase (SAMDC), and to decrease the cellular level of the polyamine putrescine (Thomas T. et al., 1999).

Tumors:
- In a cohort of 50 primary human breast cancers, ODC activity level appeared to be a negative independent prognostic factor for both disease-free survival and overall survival. With regard to overall survival, the adverse influence of ODC expression was superior even to that provided by the number of positive nodes. Furthermore, the statistical significance of the ODC effect on survival was enhanced when breast cancer-specific mortality was included in the analysis as opposed to death from any cause (Manni A. et al., 1996).

- The expression ODC mRNA in 53 cases of breast cancer by RT-PCR. A significantly higher expression of ODC mRNA was, observed in younger patients than in older patients. The patients with a larger sized tumour possessed a significantly higher expression of ODC mRNA. In addition, the cases with a poor prognosis showed significantly higher expression of ODC. Previous studies have reported in vivo and in vitro correlation between the expression of ODC and c-myc genes in human carcinomas. We disclosed a significant correlation between these genes in primary breast carcinomas (Mimori K. et al., 1998).

- ODC activity and polyamine concentration were measured in samples from benign breast diseases (n=36), benign breast tissue adjacent to the primary carcinoma (n=19), and breast carcinoma (n=104). ODC activity in primary carcinoma was significantly higher than that found in benign breast or in breast tissue adjacent to the primary carcinoma. The total polyamines (putrescine, spermidine, spermine) content of breast cancer was higher than in benign breast tissue and correlated well with ODC activity. ODC activity correlated with histological grade, peritumoral lymphatic or blood vessel invasion, S-phase fraction, and cathepsin D. Total polyamine concentration increased with S-phase fraction, cathepsin D, and aneuploidy. No significant correlation was found between ODC or polyamines and tumor size, lymph node involvement, or steroid receptor (ER, PgR) status (Cañizares F. et al., 1999).

Auvinen M. et al. (1992) Ornithine decarboxylase activity is critical for cell transformation. Nature 360, 355-358.
Auvinen M. (1997) Cell transformation invasion and angiogenesis: a regulatory role for ornithine decarboxylase and polyamines? J. Natl. Cancer Inst. 89, 533-537.
Cañizares F. et al. (1999) Prognostic value of ornithine decarboxylase and polyamines in human breast cancer: correlation with clinicopathologic parameters. Clin. Cancer Res. 5, 2035-2041.
Hickok N.J. et al. (1987) Complete amino acid sequence of human ornithine decarboxylase deduced from complementary DNA. DNA 6, 179-187.
Huber M. and Poulin R. (1996) Post-translational cooperativity of ornithine decarboxylase induction by estrogens and peptide growth factors in human breast cancer cells. Mol. Cell. Endocrinol. 117, 211-218.
Manni A. et al. (1996) Prognostic influence on survival of increased ornithine decarboxylase activity in human breast cancer. Clin. Cancer Res. 2, 1901-1906.
Mimori K. et al. (1998) Expression of ornithine decarboxylase mRNA and c-myc mRNA in breast tumours. Int. J. Oncol. 12, 597-601.
Moshier J.S. et al. (1993) Transformation of NIH/3T3 cells by ornithine decarboxylase over-expression. Cancer Res. 53, 2618-2622.
Radford D.M. et al. (1987) Mapping the ornithine decarboxylase gene (ODC1 and ODC2) to 2p25 and 7q31-qter, respectively. Cytogenet. Cell Genet. 46, 678 only.
Russell D.H. (1985) Ornithine decarboxylase: a key regulatory enzyme in normal and neoplastic growth. Drug Metab. Rev. 16, 1-88 (Review).
Shantz L.M. et al. (1994) Overproduction of ornithine decarboxylase caused by relief of translational repression is associated with neoplastic transformation. Cancer Res. 54, 2313-2316.
Smith M.K. et al. (1997) Ornithine decarboxylase overexpression leads to increased epithelial tumor invasiveness. Cancer Res. 57, 2104-2108.
Thomas T. et al. (1991) Variations in amplification and expression of the ornithine decarboxylase gene in human breast cancer cells. Breast Cancer Res. Treat. 19, 257-267.
Thomas T. et al. (1999) Effects of epidermal growth factor on MDA-MB-468 breast cancer cells: alterations in polyamine biosynthesis and the expression of p21/CIP1/WAF1. J. Cell. Physiol. 179, 257-266.
Winqvist R. et al. (1986) Human ornithine decarboxylase sequences map to chromosome regions 2pter-p23 and 7cen-qter but are not coamplified with the NMYC oncogene. Cytogenet. Cell Genet. 42, 133-140.
Wright P.S. et al. (1995) Regulation of ornithine decarboxylase mRNA levels in human breast cancer cells: pattern of expression and involvement of core enhancer promoter element. Cell Growth. Differ. 6, 1097-1102.

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